In-silico discovery of CYP2E1 inhibitors from Satureja hortensis L. for urethane-induced mutagenesis: Molecular docking to MD simulation and MM/GBSA energy calculation

Abstract

Backgrounds: Urethane is a potent environmental mutagen whose bioactivation is primarily mediated by cytochrome P450 2E1 (CYP2E1). The phytoconstituents of Satureja hortensis L. have been traditionally recognized for their medicinal value, but their molecular interactions with CYP2E1 remain underexplored. Methods: Approximately 360 phytochemicals were retrieved from the IMPPAT database, duplicates and non-drug-like molecules were filtered, and drug-likeness properties were evaluated using ADMETLab 3.0. Molecular docking, molecular dynamics (MD) simulation (100 ns), free energy landscape (FEL) mapping, and binding free energy calculations were performed to characterize CYP2E1–ligand interactions. Results: Drug-likeness profiling screened the phytoconstituents for molecular docking study. Docking predicted stable binding affinity (−8.6 kcal/mol) of alpha-curcumene in the CYP2E1 active pocket through hydrophobic and π–π interactions with PHE46, TRP214, LEU217, and LEU228. MD simulations confirmed the dynamic stability of the complex with minimal deviations and stable solvent-accessible properties. FEL and principal component analysis (PCA) revealed confinement of the complex to low-energy conformational states. The binding free energy (ΔG_bind = −75.31 ± 3.1 kcal/mol) was dominated by van der Waals and lipophilic interactions, corroborating its strong binding affinity. Comparative analysis showed alpha-curcumene to be more stable and energetically favorable than other S. hortensis phytoconstituents. Conclusion: Integrated computational analysis demonstrates that alpha-curcumene from S.hortensis L. exhibits strong and stable interaction with CYP2E1, suggesting a mechanistic basis for its potential protective role against urethane-induced mutagenesis. Thesefindings position alpha-curcumene as a promising bioactive candidate, warranting furtherin vitro and in vivo validation.